Clocks, criteria and critical genes.
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Circadian Rhythm↗
Biomedical subjects
R J Lucas
Publications and source records attributed to R J Lucas.
Photoentrainment in mammals: a role for cryptochrome?
There is growing evidence in support of the hypothesis that, in mammals, photoreceptive tasks are segregated into those associated with creating a detailed visual image of the environment and those involved in the photic regulation of temporal biology. The hypothesis that this segregation extends to the use of different photoreceptors remains unproven, but published reports from several mammalian species that circadian photoentrainment survives a degree of retinal degeneration sufficient to induce visual blindness suggest that this may be so. This has lead to speculation that mammals might employ a dedicated 'circadian photoreceptor' distinct from the rod and cone cells of the visual system. The location and nature of this putative circadian photoreceptor has become a matter of conjecture. The latest candidates to be put forward as potential circadian photopigments are the mammalian cryptochrome proteins (CRY1 and 2), putative vitamin-B2 based photopigments. To date, published experimental evidence falls short of a definitive demonstration that these proteins form the basis of circadian photoreception in mammals. Consequently, this review aims to assess their suitability for this task in light of what we know regarding the biology of the cyrptochromes and the nature of mammalian photoentrainment.
Animals↗
Free running circadian rhythms of melatonin, luteinizing hormone, and cortisol in Syrian hamsters bearing the circadian tau mutation.
The tau mutation of Syrian hamsters induces a robust reduction in the period of circadian activity rhythms, from 24 h (wild-type; tau++) to 22 h (heterozygote; tauS+) and 20 h (homozygous mutant, tauSS). Here, we examine the effect of this mutation on circadian rhythms of LH, melatonin, and cortisol in ovariectomized hamsters. Free running circadian rhythms were observed in all three hormones. In each genotype, endocrine rhythms were synchronized with concurrently assessed activity rhythms, suggesting a shared period around 20 h in tauSS, 22 h in tausS+, and 24 h in tau++. Phasing with respect to the activity rhythm was generally similar in tau++ and mutant genotypes. However, melatonin concentrations rose significantly earlier in tauSS than in tau++ animals. Explanted pineals from both genotypes exhibited a similar time course of response to norepinephrine administration, suggesting that the phase advance of melatonin production observed in tauSS in vivo is not a direct effect of the tau mutation within the pinealocyte. The demonstration of reduced period endocrine rhythms in the mutant genotypes extends previous behavioral studies and, together with recent work on rhythmicity in the isolated retina, suggests an ubiquitous influence of the tau mutation on the processes of circadian rhythm generation in this species.
Animals↗
Neither functional rod photoreceptors nor rod or cone outer segments are required for the photic inhibition of pineal melatonin.
Pineal melatonin production is rapidly suppressed by light. In mammals, the photoreceptors mediating this response are ocular; however, definitive information regarding their nature and precise location is absent. In an attempt to define these photoreceptors, we examined the sensitivity of pineal melatonin production to inhibition by controlled irradiance monochromatic green light (lambda max 509 nm) in C3H mice bearing either of two mutations affecting the retina: retinal degeneration (rd), a disruption of rod phototransduction, and retinal degeneration slow (rds), an ablation of photoreceptor outer segments. Diurnal profiles of pineal melatonin content were similar in both mutant genotypes and in wild-type mice; melatonin peaked between 3-5 h before lights on. All three genotypes exhibited irradiance dependent inhibition of pineal melatonin content; 2.6 x 10(-2) microwatts/cm2 509 nm light induced complete suppression in all three genotypes, whereas lower irradiances were ineffective in all cases. Bilateral enucleation abolished responses even to 6 microwatts/cm2 509 nm light. These results demonstrate that the process of irradiance detection for pineal melatonin inhibition is buffered against considerable loss of photoreceptive capacity and that neither rod photoreceptors nor rod or cone outer segments are required for mediating this response in mice.
Animals↗
C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption.
1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.
Administration, Oral↗
Expression of vasoactive intestinal peptide mRNA in the suprachiasmatic nuclei of the circadian tau mutant hamster.
The tau mutation of the Syrian hamster is one of only two mutations currently known to affect the circadian system in mammals. In order to investigate the molecular mechanisms associated with this mutation, we have compared the level of expression of the mRNA for vasoactive intestinal peptide (VIP) in the suprachiasmatic nuclei (SCN) and cerebral cortex of homozygous tau mutant and wild-type animals using in situ hybridization histochemistry. We observed no significant circadian variation in this message within the SCN, cingulate cortex or parietal cortex of either genotype. Comparison between genotypes indicated a significantly higher signal for VIP mRNA in the SCN of tau animals. This phenotypic effect within the SCN raises the possibility that some of the circadian consequences of the tau mutation are associated with an increased expression of the VIP gene.
Animals↗
Conservative surgery and radiation therapy for infiltrating lobular carcinoma of the breast. The role of preoperative mammograms in guiding treatment.
BACKGROUND: The authors have reviewed their institution's experience with conservative surgery and radiation therapy for early stage breast cancer with the goal of defining the impact of infiltrating lobular histology (ILC) on the local recurrence rate. Also, they have examined the preoperative mammograms of the ILC patients to determine if mammographic features could be used to predict treatment outcome. METHODS: Between January 1, 1980, and December 31, 1987, 402 cases of Stages I and II breast cancer were treated with conservative surgery and radiation therapy (BCT) at William Beaumont Hospital. Each patient had at least an excisional biopsy. Radiation consisted of 45-50 Gy to the entire breast followed by a supplemental boost dose, so that a minimum of 60 Gy was delivered to the tumor bed. Thirty cancers were classified histologically as infiltrating lobular carcinoma (ILC), 346 as infiltrating ductal carcinoma (IDC), and 26 as other. Median follow-up is 60 months. RESULTS: There was no significant difference in 5 year actuarial local recurrence rates between ILC and IDC, 3.3 versus 4.2%, respectively, (P = not significant). Preoperative mammograms were retrospectively reviewed for 29 of the 30 ILC patients. A spiculated opacity was the most common primary mammographic finding (63%), followed by architectural distortion (17%), poorly defined opacity (7%), and negative (7%). Of the patients who had a preoperative primary mammographic finding of a spiculated opacity, 55% underwent reexcision after the initial excisional biopsy, and residual invasive carcinoma was found in 18% of the reexcision specimens. In contrast, of the patients with a primary mammographic finding of an architectural distortion, poorly defined opacity, or negative, 89% underwent reexcision after an initial excisional biopsy, and residual invasive carcinoma was found in 100% of the reexcision specimens. CONCLUSIONS: Infiltrating lobular carcinoma does not have a worse local recurrence rate compared with IDC when each is treated with breast-conserving therapy. The primary finding on preoperative mammograms in patients with ILC may prove to be a useful tool for predicting the likelihood of residual carcinoma in the breast after initial excisional biopsy.
Adult↗
Polydisperse scattering theory and comparisons with data for red blood cells.
Recent results for low-frequency scattering by polydisperse distributions of correlated low-refracting particles averaged over orientation are analyzed numerically. The roles of shape and correlations (parameterized by c) and polydispersity (specified by the normalized variance d in size governed by the gamma probability density) are investigated. The key variable is the net volume fraction w occupied by the particles. The incoherent scattering is determined by delta = PS(c,d;w) with P as a particle population factor that is independent of w, and S as the fluctuation-correlation function of w. Earlier applications of monodisperse (d = 0) theory emphasized the influence of c on the peak delta = delta and its location w = w in order to invert ultrasonic scattering data of Shung and his associates for red blood cell suspensions under different flow conditions. For d greater than 0, comparable curves for delta (w) decrease more gradually with w increasing past w (because of additional scattering arising from polydispersity) and thereby provide better fits to data for the more controlled flows over broader ranges of hematocrit.
Acoustics↗
Nonoperative management of the adult ruptured spleen.
The risk of postsplenectomy sepsis has led to increased enthusiasm for preservation of the spleen. From January 1984 to December 1988, 51 consecutive adult patients with ruptured spleen sustained from blunt trauma were examined. Thirty-four patients (67%) had their conditions hemodynamically stabilized at the time of hospital admission and were placed on a regimen of strict bed rest with intensive monitoring. The average hemoglobin value at hospital admission in this group was 126 +/- 18 g/L, with an average drop of 17 +/- 14 g/L during their hospitalization; 14 patients required transfusions averaging 3 U each. Nonoperative treatment was successful in 33 (97%) of 34 patients; one patient whose condition deteriorated clinically underwent splenectomy on the fifth hospital day. These patients have been followed up for an average of 28 months with no sequelae from their splenic injury. We conclude that a nonoperative approach is a viable alternative in stable adult patients with splenic injuries due to blunt trauma when intensive monitoring is available.
Adult↗
Unilateral neck exploration for primary hyperparathyroidism.
The operative approach to primary hyperparathyroidism due to a single adenoma remains controversial. We evaluated our experience with 75 patients presenting with primary hyperparathyroidism between January 1979 and September 1988. Prior to 1985 all patients underwent bilateral exploration. During this period, ultrasonographic localization in 6 patients proved highly accurate. Subsequently, routine preoperative ultrasonographic localization was used and patients were prospectively evaluated for the following: (1) incidence of unilateral exploration, (2) accuracy of ultrasonographic localization, (3) incidence of complications, and (4) operative time. Localization permitted unilateral exploration in 19 of 36 patients, although its accuracy depended on the interest of the radiologist involved. Institution A had an accuracy of 92%, while institution B had an accuracy of only 43%. There were fewer complications with unilateral exploration, and operative time was significantly less. Unilateral exploration based on preoperative ultrasonographic localization is recommended as the initial approach to primary hyperparathyroidism due to a single adenoma.
Adenoma↗
Kinetic properties and contribution to cellulose saccharification of a cloned Pseudomonas beta-glucosidase.
The plasmid pND71, which encodes beta-glucosidase (cellobiase) activity, cloned from the cellulolytic Pseudomonad, PS2-2, was mobilized by conjugation into 10 Pseudomonas strains. The highest specific activity was produced by 17498 (pND71) and the properties of the enzyme produced from this transconjugant were studied. The enzyme was shown to be cell associated, to have a temperature optimum of 37 degrees C, a pH optimum of 7.0 and Km values of 1.33 and 2.94 mM for pNPG and cellobiose respectively. It was competitively inhibited by glucose, with a Ki of 30 mM. Evidence was obtained which suggested that the enzyme was produced constitutively and that synthesis was not repressed by glucose. When culture preparations were used in combination with Trichoderma reesei QM9414 and C30 enzyme preparations to saccharify cellulose, 17498 (pND71) was more effective than preparations of PS2-2 in acting synergistically with T. reesei to solubilize more carbohydrate and produce more glucose.
Carbohydrate Metabolism↗
Hepatic resections: an eight year experience at a community hospital.
Between April 1979 and March 1987 24 patients underwent 26 hepatic resections. Colorectal liver metastases constituted the largest group (n = 18), followed by hepatocellular carcinoma (n = 2), Echinococcal liver cyst (n = 1), cholangiocarcinoma (n = 1), and leiomyosarcoma (n = 1). The mean age was 41.8 +/- 14.6 years (range: 23-69 years). Fifteen women and nine men comprised the group. The operative morbidity was 21 per cent, the 30-day operative mortality was 8 per cent (two deaths). Both operative deaths occurred in patients with colorectal liver metastases. The 18 patients with colorectal liver metastases included ten women and eight men. The mean age was 59.1 +/- 6.5 years (range: 46-69 years). There were seven synchronous and 11 metachronous liver metastases. Carcinoembryonic antigen (CEA) was found elevated in 14 of the original primary colonic carcinomas, and in all but one patient with metachronous liver metastases. The mean time from colorectal carcinoma resection to occurrence of metachronous metastases was 17.1 +/- 5.8 months. To date, 10 patients have had recurrences of liver metastases after hepatic resection for colorectal liver metastases. The mean time of recurrence was 12.6 +/- 11.9 months. The size of the metastases was 3.8 +/- 3.2 cm (range: 0.2-17 cm). The mean number of lesions present was 1.5 +/- 1.0. The 1 year and 2 year actuarial survival rates were 87.5 and 43.8 per cent respectively. The longest survivor is alive 54 months after his hepatic resection for colorectal liver metastases and remains to this date disease free.(ABSTRACT TRUNCATED AT 250 WORDS)
Actuarial Analysis↗
Inversion of ultrasonic scattering data for red blood cell suspensions under different flow conditions.
Recent results for low-frequency scattering by correlated random distributions of nonspherical particles averaged over orientation are applied to invert ultrasonic data for red blood cell suspensions under different flow conditions. The inversion procedure isolates a correlation parameter (c) representing a process in which the volume fraction (w) of particles increases linearly, and also a cell population parameter P. Reduced data records of scattering versus hematocrit are compared with S(c;w)P, where the generalized fluctuation function S is proportional to the variance in particle number, and P is proportional to the backscattering cross section of an isolated particle. The peak scattering for the different flow processes occurs at values of w ranging from about 0.15 for the most uniform to 0.25 for the least, corresponding to c values of about 2.1 to 0.4, as compared with w approximately equal to 0.13 and c = 3 for hard (repulsive at contact) spheres or aligned ellipsoids. The lower values of c suggest weaker repulsion between the deformable cells and effective interparticle attraction (aggregative trends), and c approximately equal to 2 may also involve flow alignment of the discoids.
Animals↗
Gastrocolic fistula caused by benign gastric ulcer in the patient who has not had prior operation. Case reports and review of the literature.
Gastrocolic fistula caused by benign gastric ulcer is an intriguing condition when it occurs in the patient who has not had prior operation. Four such cases are presented here and similar past cases are reviewed. The authors recount the history of surgical thought concerning this disorder and make recommendations for the preoperative and intraoperative approach to these patients.
Adult↗
A nonoperative approach to the adult ruptured spleen sustained from blunt trauma.
From 1978 to 1983, 53 consecutive adult patients with ruptured spleens documented by radionuclide studies, computerized axial tomography, or surgery, were evaluated at William Beaumont Hospital. Thirty-four patients (64%) underwent an exploratory laparotomy; 33 resulted in a splenectomy and one patient had an attempted splenorraphy which failed. Nineteen patients (36%) were hemodynamically stable on admission, or had transient episodes of hypotension readily reversed by intravenous fluids. They were placed at strict bedrest under intensive monitoring. Two patients deteriorated clinically and were taken to surgery, resulting in a splenectomy on the fourth and sixth hospital day, respectively. Seventeen patients (32%) were successfully treated nonoperatively, representing an 89 per cent success rate. The average admitting hemoglobin in the nonoperative group was 13.2 gm/dl, with an average drop of 1.6 gm/dl, and an average total blood transfusion of 1.2 units. These patients were followed for an average of 19.2 months, with no sequelae from their splenic injury. In a hemodynamically stable adult patient with a splenic injury sustained from blunt trauma, a nonoperative approach is a viable alternative when close intensive monitoring is available.
Adolescent↗
Isolated ischemic necrosis of the cecum in patients with chronic heart disease.
Isolated ischemic necrosis of the cecum is an infrequently described entity. We report three cases seen at our institution within a three-year period. All three patients had been hospitalized for congestive heart failure in the past, but none was in failure at the time of the most recent hospitalization. All three patients presented with clinical and laboratory findings consistent with acute appendicitis. At surgery the cecum was ischemic in each case, while the appendix and the remainder of the intestine appeared normal. There was no evidence of major vascular occlusion or embolization at the time of original operation. We propose that the cecum, like the splenic flexure, is a "watershed area," with poor blood supply relative to that of the adjacent intestine. While cecal ischemia has been described in association with a variety of clinical entities, we propose a newly recognized association with poor myocardial function. In such patients, isolated ischemic necrosis of the cecum should be considered in the differential diagnosis of right lower quadrant pain.
Aged↗
Management of high bile duct carcinoma.
Based on experience with six patients with high bile duct carcinoma, a rational therapeutic approach is proposed. When extent of tumor precludes resection, the authors recommend palliation with a biliary-enteric anastomsis to avoid the complications and inconveniences of long-term transhepatic stenting. This is best accomplished with construction of a left cholangiojejunostomy using the round ligament approach. Temporary bilobar decompression may be necessary in select cases.
Adenocarcinoma↗
Fluorophotometric evaluation of capillary permeability in gram-negative shock.
We developed a new method by which capillary permeability changes secondary to gram-negative sepsis can be easily monitored. In a preliminary trial, ten dogs were injected intravenously with live Escherichia coli. Progressive extravasation of fluorescein from the retinal capillary bed was demonstrated by retinal angiography, thus indicating "capillary leak." In a subsequent trial, fluorophotometry facilitated direct quantitation of this leak. Three control and three septic dogs underwent continuous hemodynamic and physiologic monitoring. Hourly retinal fluorophotometric measurements were recorded. The control group demonstrated no capillary leak nor any change in hemodynamic and physiologic status. In the septic group, there was a dramatic increase in extravascular fluorescein concentration two to four hours after E coli infusion, correlating well with hemodynamic and physiologic parameters typical of gram-negative shock.
Animals↗